Age-related gastric motor dysfunctions include reduced compliance and impaired slow wave activity. However, these dysfunctions are often underestimated due in part to nonspecific symptoms and lack of sufficient medical attention. Although these conditions are not themselves fatal, they have been shown to contribute to early satiety and consequent reduced food intake. Surprisingly, recent reports have linked low dietary intake to increased cancer mortality and overall mortality in elderly individuals and aged mice, suggesting that reduced food intake due to gastric dysfunctions may contribute to increased overall mortality in elderly individuals. Thus, a growing body of evidence indicates the significance of studying age-related gastric motor dysfunctions to promote healthy aging. Previously we reported a profound age-related loss of interstitial cells of Cajal (ICC), pacemaker and neuromodulator cells of the GI tract. ICC loss was accompanied by a depletion of ICC stem cells (ICC-SC); and these changes could be linked to specific gastric dysfunctions and reduced food intake. A critical gap in our knowledge is the lack of understanding of the mechanisms of age-related ICC loss and related gastric motor dysfunctions. Stem cell senescence has been proposed as a major factor of aging-related organ dysfunctions, and in preliminary studies we found that overactive Wnt/?-catenin signaling can indeed lead to ICC-SC senescence via increased Trp53. Another important mechanism proposed to underlie stem cell senescence is altered function of histone methyltransferase enhancer of zeste homolog 2 (Ezh2), which we found to be upregulated in senescent ICC-SC and gastric tissues obtained from older mice and individuals. However, the relationship between Wnt-induced senescence and Ezh2 remains unclear. Therefore, my overall hypothesis is that ICC-SC senescence, a putative mechanism of age-related ICC loss, is due to overactive Wnt signaling-induced recruitment of Ezh2 and consequent repression of genes important for ICC- SC self-renewal and differentiation; and senescence can be prevented by Ezh2 inhibition. Specific Aim 1 is to provide definitive evidence that overactive Wnt signaling can lead to ICC-SC senescence via Trp53 upregulation. Specific Aim 2 is to unravel epigenetic mechanisms of ICC- SC senescence underlying aging-associated ICC depletion. Specific Aim 3 is to determine the functional consequence of aging-associated ICC depletion. This project may reveal a novel, pharmacologically realizable therapeutic approach to prevent ICC-SC senescence and age- related gastric dysfunctions leading to improved quality of life. This project also aims to discover a previously unrecognized mechanism of stem cell aging, which may be of general significance.